Janman, Daniel; (2019) Understanding the pathways that regulate the intracellular trafficking of CTLA-4. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

T cell activation is dependent on two main signals; signal one via the TCR binding to its cognate antigen presented by MHC on the surface of APCs, and signal two through costimulatory receptors such as CD28 binding to its ligands CD80 and CD86. CTLA-4 forms a vital checkpoint in the regulation of T cell activation, by binding to and removing CD80 and CD86 from the surface of APCs via the process of transendocytosis. Although CTLA-4 needs to be on the surface of the T cell to interact with its ligands, the majority of CTLA-4 protein is found in intracellular compartments due its interesting and poorly defined trafficking pathway. In this study I show that specific motifs within the cytoplasmic tail of CTLA-4 are involved in the regulation of CTLA-4 trafficking. This work also shows that CTLA-4 is trafficked through early and late endosomes on route to lysosomes for degradation, and through early and recycling endosomes and possibly the TGN for its recycling route. These degradation and recycling pathways are regulated by Rab5 and Rab7, and Rab5 and Rab11 respectively. Furthermore, I demonstrate that LRBA is involved in the fate decision between these pathways, and provide direct evidence for the role of LRBA in CTLA-4 recycling.

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